Optical coherence tomography (OCT) is an emerging imaging technology which performs high resolution, cross-sectional and three-dimensional (3D) imaging of tissue morphology in situ and in real time. Optical coherence microscopy (OCM) combines OCT with confocal microscopy to achieve cellular level resolution with an extended imaging depth. The hypothesis is that OCT and OCM can function as a type of optical biopsy to visualize early neoplastic changes in vivo without excision and processing of specimens. If successful, these imaging technologies could guide biopsy to reduce sampling error and improve sensitivity. This program vertically integrates technology development, biomedical research and clinical studies in a collaborative effort between investigators at the Massachusetts Institute of Technology, Beth Israel Deaconess Medical Center, Boston VA Healthcare System, and Harvard Medical School. The specific aims are: 1. Develop Ultrahigh Resolution 3D-OCT Imaging Technology. 3D-OCT will enable new visualization techniques such as generation of arbitrary cross-sectional images, projection views similar to microscopy, improved quantitative measurements of morphology and virtual manipulation of tissue for visualizing structure. We propose to develop new technology for clinical endoscopic 3D-OCT to achieve imaging speeds of 500,000 axial scans / second with <5 m axial image resolution, factors of ~100x faster speed and ~2-3x finer resolution than standard OCT. 2. Develop Endoscopic Optical Coherence Microscopy (OCM) for Cellular Level Imaging. Developing techniques for cellular resolution endoscopy is a longstanding challenge in biomedical imaging and promises to improve early diagnosis of cancer. Optical coherence microscopy (OCM) is an in vivo cellular imaging technique which combines OCT with confocal microscopy. We propose to develop new OCM technology to enable cellular level endoscopic imaging. 3. Ex Vivo Imaging Studies Using 3D-OCT and OCM. Ex vivo imaging is a powerful methodology to establish correlations between OCT and OCM diagnostic features and histopathology. We will investigate upper and lower Gl tract pathologies including Barrett's esophagus, dysplasia, and adenocarcinoma, as well as dysplasia and adenocarcinoma in inflammatory bowel disease. We will also investigate breast malignancies. These studies will establish correspondence with histology, develop new visualization methods, validate computer assisted tissue classification techniques, and assess pilot applications in new pathologies. 4. Clinical Endoscopic Imaging of the Upper and Lower Gastrointestinal Tract. The hypothesis of this aim is that 3D-OCT and OCM imaging in the gastrointestinal tract can identify neoplastic changes. We will investigate Barrett's esophagus, dysplasia, and adenocarcinoma in the upper GI tract and dysplasia and adenocarcinoma of the colon in inflammatory bowel diseases in the lower GI tract. If successful, the proposed research will develop and demonstrate new imaging technology which will augment gastrointestinal endoscopy and open the door for improved detection of a wide range of neoplasias.